Alessandro Biffi is a Behavioral Neurologist and Neuropsychiatrist at Massachusetts General Hospital (MGH), whose career goal is to become a leading clinician-investigator in the field of the neuropsychiatric manifestations of cerebrovascular disorders. In preliminary studies, Dr. Biffi has found that apathy and depression develop with high frequency in survivors of Intracerebral Hemorrhage (ICH). Furthermore, development of these neuropsychiatric disorders substantially increases risk for a combined subsequent endpoint including death, stroke and dementia. Prevention of apathy/depression after ICH may therefore represent a novel strategy to improve long-term outcome after ICH. The proposed project addresses key unresolved questions that must be answered in order to designs trials of apathy/depression prevention after ICH. These questions are: 1) what is the relationship between post-ICH apathy/depression (PIA/D) and each key individual outcome for the patient (death, recurrent ICH, ischemic stroke, dementia)?; 2) which biological processes responsible for PIA/D could be targeted with novel prevention strategies? Dr. Biffi has specifically singled out anatomical ICH characteristics, underlying neurodegenerative/cerebrovascular chronic conditions and long-term blood pressure control as biological mechanisms for investigation. Addressing these questions is made all the more pressing by the lack of prior studies of post-ICH apathy/depression. Published studies of stroke-related neuropsychiatric sequelae focused almost exclusively on ischemic stroke, and are therefore unable to address ICH-specific biological mechanisms (e.g. the role of hydrocephalus and intraventricular hemorrhage in predicting apathy/depression risk). Dr. Biffi established an early-career track record investigating the epidemiology of cerebrovascular conditions, and acquiring expertise in genomics and bioinformatics in the process. He also generated preliminary data supporting the feasibility of the proposed research, as part of a mentored R25 award. The proposed K23 award will train Dr. Biffi in selection, capture and interpretation of cognitive and neuropsychiatric measures, health data remote monitoring, and advanced neuroimaging techniques. To this end, Dr. Biffi has assembled a team of experts in all aforementioned areas, leveraging the extensive resources and exceptional environment of Massachusetts General Hospital / Harvard Medical School. Dr. Jonathan Rosand will serve as primary mentor, and coordinate a team of highly experienced co-mentors including Drs. David Bennett, Anand Viswanathan, Deborah Blacker, David Salat, Kamal Jethwani and Janet Sherman. This award will provide Dr. Biffi with the skills to evolve into an independent clinician-investigator, focused on prevention of neuropsychiatric disorders in cerebrovascular diseases - with specific emphasis on apathy/depression prevention to improve long-term outcome after intracerebral hemorrhage.